This invention relates to certain imidazo[1,2-a]pyrazin-8-ylamines and related compounds, which when appropriately substituted are modulators of kinase activity. This invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of kinase-associated disorders. Additionally, this invention relates to the use of such compounds as probes for the identification of kinases of therapeutic interest.
One of the central post-translational control elements in eukaryotic signal transduction is the phosphorylation of the hydroxyl moiety of serine, threonine, or tyrosine. The phosphorylation state of a given protein can govern its enzyme activity, stability, protein-protein binding interactions, and cellular distribution. Phosphorylation and dephosphorylation is thus a “chemical switch”, which allows the cell to transmit signals from the plasma membrane to the nucleus and to ultimately control gene expression. Although the exact mechanisms of signal transduction have yet to be elucidated, kinases are involved in the control of cell metabolism, growth, differentiation, and apoptosis. These signaling mechanisms affect the onset of cancer, metabolic disorders (for example diabetes), inflammation, immune system disorders, and neurodegeneration. Certain kinases have been implicated in cell proliferation and carcinogenesis. For example, many human cancers are caused by disregulation of a normal protein (e.g., when a proto-oncogene is converted to an oncogene through a gene translocation). Because kinases are key regulators they are ideal drug design targets. Inhibitors of kinases are among the most important pharmaceutical compounds known. Tyrosine kinase inhibitors are useful in inhibiting T-cell proliferation, and thus they are useful as immunosuppressive agents for the prevention or treatment of graft rejection following transplant surgery and for the prevention or treatment of autoimmune diseases such as rheumatoid arthritis and psoriasis. Other tyrosine kinase inhibitors have been described, for example, in U.S. Pat. No. 5,593,997 to Dow et al. Erlotinib (CP-358774) is a quinazoline derivative under development as an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for treatment of solid tumors including non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and neck cancer. Gleevec and Imatinib (STI-571), from Novartis, are tyrosine kinase inhibitors indicated for treatment of chronic myelogenous leukemia (CML), prostate tumors, and gastrointestinal stromal tumors, among others. AstraZeneca is developing gefitinib (ZD-1839; Iressa), an inhibitor of epidermal growth factor receptor 1 (EGFR1) tyrosine kinase, for the potential treatment of cancers which over-express EGF receptors, including non-small cell lung cancer (NSCLC) and other solid tumors such as breast tumors. CEP-1347 (Cephalon Inc.) is an indolcarbazole choline acetyltransferase inhibitor and c-jun N-terminal kinase inhibitor for treatment of Alzheimer's disease, Parkinson's disease, and AIDS-related peripheral neuropathy. Cephalon is also developing CEP-701, an orally active tyrosine kinase inhibitor for the potential treatment of prostate and other cancers. A PDGF receptor tyrosine kinase inhibitor (SU-101, leflunomide) is being investigated for treatment of various cancers and rheumatoid arthritis. Sugen has also investigated the anti-cancer effects of the FLK-1 tyrosine kinase inhibitor Semaxanib, particularly for colorectal and lung cancers, leukemia, Kaposi's sarcoma, and others.
Serine/threonine kinase inhibitors are also pharmaceutically important. Eli Lilly is developing LY333531 (ruboxistaurin), an inhibitor of protein kinase C beta, for treatment of diabetic macular edema and diabetic retinopathy. Flavopirodol (Aventis) is a synthetic flavonoid inhibitor of cyclin-dependent kinases, is under development for treatment of mantle cell lyrnphoma (MCL) and fludar refractory chronic lymphocytic leukemia (CLL). One Raf kinase inhibitor (BAY-43-9006, Bayer) is in development for treatment of solid tumors and myeloid leukemia, and another (ISIS 5132, Isis) is being investigated for treatment of ovarian cancer. Several p38 mitogen-activated protein kinase inhibitors (VX-745, VX-702, and VX-850, Vertex, and SCIO-469, Scios) have been investigated for treatment of inflammation, rheumatoid arthritis, and myelodysplastic syndrome (MDS).
Highly selective, cell-permeable modulators of one or more individual kinases would thus be useful in the treatment of various kinase-implicated disorders. Such compounds would also be useful for the systematic investigation of the cellular function of one or more kinases, and thus, would provide invaluable tools for the identification of various kinases of therapeutic interest.
The compounds most closely related structurally to those described herein are a series of imidazolopyrazines described in WO 02/060492, as JAK inhibitors for the treatment of immune disorders. A series of piperazinylimidazo[1,2a]pyrazines are described by Lumma J. Med. Chem. 1983, 26, 357–363 as displaying affinity for α-adrenergic receptors. Other imidazo[1,2-a]pyrazines have been reported to be useful as bronchodilators and phosphodiesterase inhibitors (see, for example, Bioorg. Med Chem. 1999, pages 1059–1065), and as GABAA modulators (see for example WO 02/10170). Effects on pulmonary hypertension have also been reported (see, for example, J. Cardiovasc. Pharmacol. 1998, volume 32, no. 2, pages 213–219). The compounds described in these publications are not within the scope of the present invention.